Modern Pathology (2019) 32:1390–1415

https://doi.org/10.1038/s41379-019-0280-2

REVIEW ARTICLE

An update on the morphology and molecular pathology of serrated

colorectal polyps and associated carcinomas
1
Rish K. Pai ●
Mark Bettington2,3,4 Amitabh Srivastava5 Christophe Rosty
● ●
2,3,6

Received: 28 February 2019 / Revised: 28 March 2019 / Accepted: 29 March 2019 / Published online: 25 April 2019
© United States & Canadian Academy of Pathology 2019

Abstract
Our understanding of serrated colorectal polyps has increased dramatically over the past two decades and has led to a
modern classification scheme for these lesions. Sessile serrated polyps with dysplasia represent the most clinically significant
serrated polyp; however, the morphologic heterogeneity of dysplasia in sessile serrated polyps has only recently been
recognized and correlated with MLH1 immunohistochemistry. Detailed morphologic analysis of traditional serrated
adenomas has led to the recognition of flat and early forms of this polyp. Robust data on the risk of metachronous lesions in
patients with serrated polyps are also beginning to emerge. This review will summarize our current understanding of serrated
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polyps and associated carcinomas with a focus on diagnostic criteria, morphologic heterogeneity, molecular findings, and
natural history. Controversial issues in the diagnosis and classification of these polyps are also discussed.

Introduction adenoma has long been recognized as a precursor to col-

Detection and removal of premalignant lesions is the
guiding principle of colorectal carcinoma screening pro-
grams. Both colonoscopic surveillance and/or stool-based
tests are utilized in most counties but only colonoscopy
allows for resection of precursor lesions. Colonoscopy also
allows for identification of patients at higher risk for
developing metachronous lesions based on pathologic
review of polypectomy specimens. While the conventional
* Rish K. Pai
pai.rish@mayo.edu
* Christophe Rosty
c.rosty@uq.edu.au
1
Department of Laboratory Medicine and Pathology, Mayo Clinic
Arizona, Scottsdale, AZ 85259, USA
2
Faculty of Medicine, The University of Queensland,
Brisbane, QLD 4072, Australia
3
Envoi Specialist Pathologists, Brisbane, QLD 4059, Australia
4
The Conjoint Gastroenterology Laboratory, QIMR Berghofer
Medical Research Institute, Brisbane, QLD 4006, Australia
5
Department of Pathology, Brigham and Women’s Hospital,
Boston, MA 02115, USA
6
Department of Pathology, University of Melbourne,
Melbourne, VIC 3010, Australia
orectal carcinoma and served as the primary driver of post-
polypectomy surveillance guidelines, work over the past
few decades has identified and characterized other precursor
lesions. It is now recognized that up to at least 20% of
colorectal carcinomas arise not through conventional ade-
nomas but rather through serrated polyps [1, 2].
Serrated polyps range in morphology from polyps with
only superficial serrations to those with exaggerated ser-
rated architecture and overt dysplasia. These polyps are also
molecularly heterogenous and can give rise to carcinomas
with divergent clinical outcomes. This review will sum-
marize the classification and molecular characterization of
serrated polyps. Key morphologic features that are neces-
sary for proper classification will be presented and unusual
serrated lesions that do not fit neatly into a specific category
will be discussed. The emerging data on the natural history
of serrated precursors will be emphasized in addition to the
features that should guide future colonoscopy surveillance
intervals. Finally, an update on serrated polyposis, as well
as colorectal carcinomas arising from serrated precursors
will be provided.
Classification and terminology
Table 1 provides a classification scheme of serrated color-
ectal polyps along with key morphologic and molecular
features. Two types of hyperplastic polyp are recognized
Table 1 Histologic and molecular features of serrated polyps
Histologic features Molecular features
Type Crypt architecture Proliferation zone Cytologic features Mucin type BRAF KRAS CpG island
mutation mutation methylation

Microvesicular Funnel-shaped crypts with Located uniformly in the Small basally located nuclei, Mixed Micro- 70–80% 0% +
hyperplastic polyp serrations limited to upper basal portion of crypts no dysplasia vesicular and Goblet
two-thirds cell
Goblet cell Elongated crypts that Located uniformly in the Small basally located nuclei, Goblet cell only 0% 50% −
hyperplastic polyp resemble enlarged normal basal portion of crypts no dysplasia
crypts; Little to no serrations
Sessile serrated Horizontal growth along the Proliferation may be Small basally located nuclei Mixed Micro- >90% 0–5% ++
polyp muscularis mucosae, abnormally located away with occasional larger nuclei vesicular and Goblet
dilation (often asymmetric) from the crypt base, variable with inconspicuous nucleoli, cell
of the crypt base (basal third from crypt to crypt no dysplasia
of the crypt), and/or
serrations extending into the
crypt base
Sessile serrated As for sessile serrated polyp As for sessile serrated polyp Varied morphologic Varied type >90% 0% +++
polyp with dysplasia with more proliferation in appearance to dysplastic
dysplastic component component
Traditional serrated Slit-like serrations, often Present within ectopic Elongated pencillate nuclei Occasional scattered 20–40% 50–70% BRAF mutated
adenoma ectopic crypt foci crypt foci and crypt base with nuclear stratification and goblet cells; rare ++
cytoplasmic eosinophilia; goblet cell variant KRAS mutated
may develop overt has been described +
(conventional or serrated)
dysplasia
Serrated adenoma- Varied Varied Unequivocal dysplasia must Varied Uncertain Uncertain Uncertain
unclassified be present
An update on the morphology and molecular pathology of serrated colorectal polyps and associated. . .
1391
1392
morphologically; however, it is not yet necessary to dis-
tinguish between these two variants in clinical practice.
Rather, it is important to recognize the subtler features of
the goblet cell variant of hyperplastic polyp (goblet cell
hyperplastic polyp) in order to distinguish this from normal
mucosa and to separate it from other types of serrated
polyps. The much more common microvesicular variant of
hyperplastic polyp has been referred to as mucosal hyper-
plasia and metaplastic polyp in the older literature; however,
those terms are no longer recommended.
Snover and colleagues first recognized an unusual ser-
rated polyp that tended to occur in patients with so-called
“hyperplastic polyposis syndrome” [3]. In 2003, Torla-
kovic et al. provided the first description of similar unusual
serrated polyps in patients without any known polyposis
syndrome and termed them serrated polyps with abnormal
proliferation [4]. Since 2003, this polyp has been known by
many names including sessile serrated adenoma, sessile
serrated polyp, sessile serrated adenoma/polyp, and more
recently sessile serrated lesion [5]. The argument for
including adenoma in the name was to emphasize that these
lesions are precursors to colorectal carcinoma; however, as
these polyps lack adenomatous epithelium, the use of the
word “adenoma” in the name has drawn criticism. To avoid
confusion with truly adenomatous polyps, recent consensus
guidelines have recommended against sessile serrated
adenoma [6]. It is likely that sessile serrated polyp (and
sessile serrated adenoma) will continue to be used, at least
in the United States, while sessile serrated lesion gains
wider acceptance elsewhere. Both sessile serrated polyp
and sessile serrated lesion are appropriate terms as long as
it is recognized by clinicians that they are two names for
the same polyp. For simplicity, sessile serrated polyp will
be used throughout this review. If dysplasia is present
within sessile serrated polyp then simply making the
diagnosis of sessile serrated polyp with dysplasia is
appropriate rather than qualifying the dysplasia as “cyto-
logic” as is necessary when using the term sessile serrated
adenoma.
Traditional serrated adenoma is the recognized term used
to describe the “serrated adenoma” reported by Longacre
and Fenoglio-Preiser in 1990 [7]. As sessile serrated ade-
noma will progressively become abandoned and replaced
by sessile serrated polyp or sessile serrated lesion, adenoma
will only be used for serrated polyps falling into the cate-
gory of the currently named traditional serrated adenoma.
Thus, serrated adenoma may therefore be a preferred and
more simple term to use in the future. These lesions have
distinctive morphologic features as described below, and we
have only recently appreciated the diversity of molecular
and morphologic alterations that can occur in a traditional
serrated adenoma. Finally, over the past few years we have
begun to recognize new and unusual dysplastic serrated
R. K. Pai et al.
polyps that do not qualify as typical traditional serrated
adenoma or sessile serrated polyp with dysplasia. Forcing
these polyps into a specific diagnostic category is premature
and for this reason a serrated adenoma-unclassified category
will be proposed by the World Health Organization com-
mittee for the 5th edition of the Classification of Tumors of
the Digestive System (personal communication).
Pathologic features of serrated polyps
Hyperplastic polyps
Microvesicular hyperplastic polyps are sessile polyps that
predominately occur in the distal large bowel. Endoscopi-
cally they are small or diminutive polyps that can be
recognized by a stellate pit pattern as described by Kudo
et al. [8]. Histologically, they are composed of serrated
epithelium with funnel-shaped, evenly spaced crypts. The
proliferative zones are confined to crypt bases imparting a
hyperchromatic appearance along with increased mitotic
figures. The cells lining the crypts are composed of variable
numbers of goblet cells and cells with abundant fine apical
vacuoles with microvesicular mucin (Fig. 1). In most cases,
the microvesicular cells predominate. The nuclei of the
surface epithelium are small, round to oval, and basally
located. The serrations are limited to the upper two-thirds of
the crypt without deep crypt serrations or abnormal basilar
crypt architecture [4]. In cross section, the serrated crypts of
microvesicular hyperplastic polyps have a uniform stellate
appearance. Based on these diagnostic criteria of micro-
vesicular hyperplastic polyp, it is clear that a diagnosis
requires specimens that are well-oriented as microvesicular
hyperplastic polyp is defined, in part, by the absence of the
abnormal crypt architecture that is seen in sessile serrated
polyp [4, 9, 10]. Deeper levels may help in the setting of
poorly oriented specimens. In the initial study by Torla-
kovic et al. [4], a mucin poor variant of hyperplastic polyp
was described; however, this mucin poor variant likely
represents an inflamed and mucin-depleted microvesicular
hyperplastic polyp rather than a distinct subtype of hyper-
plastic polyp.
Goblet cell hyperplastic polyps were also described by
Torlakovic et al. and further refined by O’Brien et al.
[4, 11]. They are often overlooked because of small size,
and their morphological alterations are often so subtle that
they are easily mistaken as surface hyperplastic change by
pathologists [12]. The majority of the cells of the surface
and crypt epithelium are goblet cells with small, uniform
basal nuclei (Fig. 1). In goblet cell hyperplastic polyps, the
crypts are taller and wider than in normal mucosa, and show
occasional branching or tortuosity that should not be mis-
taken as sessile serrated polyp. Instead of being obviously
serrated, the epithelium shows tufting that is confined to the
An update on the morphology and molecular pathology of serrated colorectal polyps and associated. . .
Fig. 1 Hyperplastic polyps.
a Microvesicular hyperplastic
polyp with uniform crypt bases
and serrations limited to the
upper two-thirds of the crypts.
b Microvesicular hyperplastic
polyp typically has a mixture of
cells with abundant
microvesicular mucin, as well as
goblet cells. c Goblet cell
hyperplastic polyp characterized
by subtle superficial serrations.
d The majority of the cells lining
the goblet cell hyperplastic
polyp crypts are goblet cells
surface epithelium and crypt orifices. The cross sections of
crypt lumen are not stellate but round [13, 14].
Sessile serrated polyp
Sessile serrated polyp can be difficult to identify at colo-
noscopy; however, awareness and specific training can
improve detection. They appear as ill-defined, sessile, and
pale lesions with an irregular shape and “cloud-like” surface
[13, 14]. There is often adherent mucin over the surface and
a rim of bubbles or fecal debris can sometimes collect at the
periphery (Fig. 2) [15]. The Kudo pit pattern is II (stellate)
in most cases and the Paris classification is predominately 0-
IIa (superficial elevated lesions) [8, 16]. Using the Narrow-
band imaging International Colorectal Endoscopic classifi-
cation, they are type 1 [17].
Sessile serrated polyp harbor a range of abnormal his-
tological features that are mostly generated by aberrant
proliferation centers [4, 18]. Unlike microvesicular hyper-
plastic polyps, sessile serrated polyps have foci of pro-
liferation both in the crypt bases and at irregular points
along the crypt lumen. Epithelial cells then spread both
luminally and basally from these proliferation centers,
which is in contrast to the orderly luminal migration of
epithelial cells in normal crypts and in hyperplastic polyps.
This loss of orderly migration, in turn gives rise to the
characteristic histological features of sessile serrated polyp,
which include at least one of the following: asymmetric
dilatation, horizontal growth of crypts along the muscularis
mucosae, and exaggerated serrations that extend deep into
1393
the crypt accompanied by basilar crypt dilatation (Fig. 2).
The majority of crypts in sessile serrated polyp, however,
do not show the typical architectural distortion. One
unequivocal sessile serrated polyp-type crypt is now advo-
cated to be sufficient for the diagnosis of sessile serrated
polyp. Symmetrical dilatation of crypt bases without other
architectural abnormalities is considered by some not suf-
ficient for the diagnosis of sessile serrated polyp; it can be
seen in some goblet cell hyperplastic polyps and other
polyps with superimposed prolapse changes. While the
distribution in the large intestine and the average size are
different between hyperplastic polyp and sessile serrated
polyp, the histological diagnosis should be primarily based
on morphologic criteria (see discussion below).
Architectural abnormalities are best appreciated at low
power. They include aberrant crypt growth along the mus-
cularis mucosae as L-shaped or inverted T-shaped crypts or
as crypts with prominent asymmetric dilation of the basal
aspect [4, 9]. Exaggerated serration manifests as piled up
and serrated tufts of epithelium at irregular intervals along
the crypt, with more basal serrations having more sig-
nificance when separating from a hyperplastic polyp. At
higher power the cytology is bland. Goblet cell and
microvesicular mucin are common and mucin containing
cells tend to out-number enterocytes. Some degree of neu-
roendocrine cell hyperplasia is usually present. An unusual
lamina propria stromal proliferation has also been asso-
ciated with sessile serrated polyp (as well as microvesicular
hyperplastic polyp). Morphologically and immunohisto-
chemically these stromal cells resemble perineurial cells and
1394 R. K. Pai et al.

Fig. 2 Sessile serrated polyp.

a Characteristic endoscopic
appearance of a sessile serrated
polyp located on top of a
mucosal fold with Paris 0-IIa
morphology and adherent
mucus. b Histologic appearance
of the endoscopically resected
sessile serrated polyp seen in
panel a. c–f Typical
morphologic features of sessile
serrated polyp characterized by
crypts with asymmetric
proliferation resulting in deep
serrations, horizontal growth
along the muscularis mucosae,
and asymmetric basilar crypt
dilatation. g A sessile serrated
polyp with herniation of serrated
crypts into the submucosa.
h Sessile serrated polyp with
perineurial-like stromal
proliferation

likely represent a reactive proliferation induced by the ser-
rated epithelium [19–21].
Immunohistochemical stains are not required for the
diagnosis of an sessile serrated polyp but are often used for
research purposes. A Ki67 stain will show an expanded
basal proliferative compartment (similar to a hyperplastic
polyp) but also with irregular foci of proliferation along the
sides of the crypt (corresponding to the aberrant
proliferation centers) [22]. CK20 shows luminal staining.
Mucin stains can be slightly variable. MUC2 is uniformly
positive and MUC5AC is positive in the majority. Scattered
MUC6 staining is a frequent finding [23, 24]. There has
been recent interest in Annexin A10 as a marker of sessile
serrated polyp [25, 26]. This stain is more likely to be
positive in sessile serrated polyps than microvesicular
hyperplastic polyps, however, interpretation is most
An update on the morphology and molecular pathology of serrated colorectal polyps and associated. . .
unreliable in the most equivocal lesions, which has been an
obstacle to widespread adoption. Markers of more advanced
molecular alterations are not seen (e.g., no loss of MLH1
expression, no over-expression or complete loss of p53 and
no over-expression or complete loss of p16).
Sessile serrated polyp with dysplasia
Sessile serrated polyp with dysplasia is the most advanced
subtype of serrated polyp and the most clinically relevant
lesion. When sessile serrated polyps progress to malig-
nancy, a critical transient step of dysplasia occurs. Sessile
serrated polyps with dysplasia are rare, representing 2–5%
of all sessile serrated polyps and <0.5% of all colorectal
polyps [27–29]. In the first descriptions of sessile serrated
polyp with dysplasia, Goldstein and Sheridan et al. reported
rare cases of small serrated polyps ‘caught in the act’ of
malignant transformation, showing high grade dysplasia
and frequent loss of MLH1 expression [30, 31]. These early
observations already pointed out the rapid malignant
transformation of these lesions. Data from a recent large
series demonstrates that sessile serrated polyps had a mean
dwell time of 17 years before progressing into sessile ser-
rated polyps with dysplasia. However, there was no dif-
ference in the mean age of patients with sessile serrated
polyps with dysplasia and patients with sessile serrated
polyps with carcinoma, supporting the concept of rapid
malignant transformation and probably explaining why
these lesions are rarely encountered endoscopically [27]. In
the past, sessile serrated polyps with dysplasia were often
reported as mixed polyps with a serrated component and a
tubular adenoma component. We now know that both
components share the same BRAF V600E mutation and
therefore represent two stages of a single lesion with
molecular abnormalities different from that of conventional
adenomas.
Like sessile serrated polyps, sessile serrated polyps with
dysplasia are more frequently diagnosed in the proximal
colon (cecum and ascending colon) with female pre-
dominance [29]. Increasing age and increasing lesion size
are associated with the development of dysplasia in sessile
serrated polyps. However, while dysplasia has been repor-
ted in upto 32% of sessile serrated polyps >20 mm [32], it
can be present in small sessile serrated polyps, sometimes
measuring <5 mm [27, 33]. From a series of 266 cases, the
median size of sessile serrated polyps with dysplasia was
12 mm, with 40% of lesions measuring <10 mm [28].
Some sessile serrated polyps with dysplasia are protu-
berant polyps with a distinctive endoscopic appearance that
can resemble conventional adenomas; other cases present as
flat or depressed lesions (Fig. 3). The histologic diagnosis of
sessile serrated polyp with dysplasia requires an abrupt
transition from an sessile serrated polyp to an area
1395
exhibiting increased complexity in crypt architecture,
associated with various forms of cytologic atypia. One
should exercise caution when considering a diagnosis of
sessile serrated polyp with dysplasia when the dysplastic
fragments do not contain adjacent non-dysplastic sessile
serrated polyp as this may represent a separate conventional
adenoma. MLH1 immunohistochemistry, as described
below, may be helpful in this setting. Two dysplastic pat-
terns were initially described in the 4th edition of the World
Health Organization classification: the adenomatous/intest-
inal type, loosely resembling dysplasia of conventional
adenoma and the serrated type, with cuboidal cells, eosi-
nophilic cytoplasm, vesicular nuclei, and prominent
nucleoli [34]. More recently, additional patterns of dyspla-
sia have been reported, making sessile serrated polyp with
dysplasia a more heterogeneous lesion than initially
recognized [28].
Architectural changes include crowding of crypts sepa-
rated by reduced amount of lamina propria, increased
complexity in crypt branching, crypt elongation, cri-
briforming, and villous architecture (Fig. 3). The degree of
crypt serration is usually different from the adjacent sessile
serrated polyp, either increased or reduced. Cytologic atypia
varies from subtle hypermucinous changes to overt dys-
plastic changes. The mucin content of dysplastic cells is
almost always different from that seen in the adjacent ses-
sile serrated polyp. Dysplastic cells tend to have a more
homogeneous mucin appearance, from complete lack of
mucin to hypermucinous phenotype. Goblet cells are often
less prominent than in the adjacent sessile serrated polyp.
Gastric-type apical mucin vacuoles are sometimes present.
The morphologic variety of sessile serrated polyps with
dysplasia has been reported by Liu et al. [28]. They
described four patterns of dysplasia including three specific
types (serrated, adenomatous, and minimal deviation) and
one not otherwise specified group to include all of the cases
not falling into one of the other categories. Like most his-
tologic classifications, the not otherwise specified group is
the prototypic and most common pattern and encompasses
the majority of cases that would be considered adenomatous
dysplasia in the 4th the edition of the World Health Orga-
nization classification. These polyps show a variety of
architectural and cytologic abnormalities that while clearly
dysplastic, do not fall neatly into any of the specific types
described below. In contrast to true adenomatous dysplasia
these polyps usually show atypia across the full depth of the
mucosa, often have variable patterns in the one polyp and
do not have the typical basophilic appearance of conven-
tional adenomas. The vast majority of these cases are
MLH1 deficient. In contrast, the polyps with truly adeno-
matous dysplasia are rare and almost always MLH1 profi-
cient leading the authors to propose that these may in fact
represent collision lesions rather than a true sessile serrated
1396 R. K. Pai et al.

Fig. 3 Sessile serrated polyp

with dysplasia. a–b Endoscopic
appearance of sessile serrated
polyps with dysplasia
demonstrating an area of
protuberant growth in a part of
an otherwise slightly elevated
lesion (a) or as a more
diffusely protuberant polyp (b).
c–h Different morphologic
appearance of dysplasia in
sessile serrated polyp including
adenomatous (c), dysplasia not
otherwise specified (d–e),
minimal deviation dysplasia
(f–g), and serrated dysplasia (h)

polyp with dysplasia [35]. Serrated dysplasia—the same as
the World Health Organization description in its 4th edition
—has tightly packed glands composed of cells with large
nuclei, prominent nucleoli, and brightly eosinophilic cyto-
plasm. The dysplasia covers the full depth of the mucosa,
and mitoses are frequent and often atypical. MLH1
expression is retained in most cases. Lastly, minimal
deviation dysplasia with subtle but noticeable architectural
and cytologic changes is described (Fig. 4). While it is
helpful diagnostically, in practice it is not entirely necessary
to subtype dysplasia in sessile serrated polyp, rather it is
important to recognize the morphologic heterogeneity of
these lesions and to be aware of the MLH1 expression in
each morphologic subgroup (Table 2).
The chance of diagnosing minimal deviation dysplasia is
higher in female patients >60 years, with history of
An update on the morphology and molecular pathology of serrated colorectal polyps and associated. . . 1397

Fig. 4 Sessile serrated polyp

with dysplasia and correlation
with MLH1 loss. a–b Sessile
serrated polyp with
adenomatous dysplasia (a) is
characterized by retention of
MLH1 (b). c–f Sessile serrated
polyp with minimal deviation
dysplasia demonstrating
increased complexity in crypt
architecture and subtle cytologic
abnormalities (c, e). MLH1
immunohistochemistry (d, f) is
recommended in order to
recognize this morphologic
variant

advanced serrated polyps or sporadic MLH1-deficient col-
orectal carcinoma. To become familiar with the minimal
deviation dysplasia pattern, staining obvious sessile serrated
polyps with dysplasia with MLH1 may be useful. Not
infrequently, areas of MLH1 loss are identified outside the
obvious dysplastic component, in what looked like other-
wise ordinary sessile serrated polyp fragments. Reviewing
these areas in hindsight will help pathologists to recognize
the subtle morphologic patterns associated with MLH1 loss.
When changes suspicious for minimal deviation dysplasia
are found in an sessile serrated polyp, we recommend a low
threshold for ordering an MLH1 immunostain to gain
familiarity with the minimal deviation pattern and to further
refine diagnostic criteria. We currently recommend that the
loss of MLH1 expression is required for the diagnosis of
sessile serrated polyp with minimal deviation dysplasia.
Further studies are needed to assess the reproducibility of
the diagnosis and whether minimal deviation dysplasia can
be diagnosed when MLH1 is retained.
Importantly, incidental loss of MLH1 expression
restricted to the base of one or a few histologically unre-
markable serrated colonic crypts should not be regarded as
sessile serrated polyp with dysplasia. In sessile serrated
polyps with minimal deviation dysplasia, loss of MLH1
expression involves the full length of multiple adjacent
crypts that always show some abnormalities on the H&E-
stained sections.
Traditional serrated adenoma
The traditional serrated adenoma is a relatively rare serrated
polyp at risk of progression to malignancy. First reported as
‘serrated adenoma’ in 1990 by Longacre and
Fenoglio–Preiser [7], traditional serrated adenoma is char-
acterized by 3 histologic features: typical eosinophilic cells
with bland elongated nuclei, slit-like serration, and ectopic
crypt foci (also called ectopic crypt formations). None of
these features is on its own specific of traditional serrated
1398 R. K. Pai et al.

Table 2 Morphologic patterns of dysplasia in sessile serrated polyps

Patterns Architectural changes Cytologic features MLH1 loss Frequencya

Dysplasia not otherwise
specified
Minimal deviation
Serrated dysplasia
Adenomatous dysplasia
a
Frequency of each pattern from Liu et al. [28] Multiple patterns can be present in a single lesion.
Easily identifiable and varied in
appearance: crypt elongation,
crowding, complex branching,
change in serration
Subtle changes with crypt
crowding, change in crypt
branching pattern and often
reduced serration
Closely packed small glands with
reduced serration and
cribriforming
Absence of crypt serration, same
appearance as conventional
adenomas; dysplastic component
on the upper part of the lesion
Obvious atypia with amphophilic or eosinophilic Frequent 79%
cytoplasm, hyperchromatic nuclei with (>80%)
pseudostratification, frequent mitotic figures and
loss of polarity
Cells with hypermucinous cytoplasm or slightly Required for 19%
eosinophilic with gastric phenotype, basally the diagnosis
located nuclei showing mild hyperchromasia and
mitotic figures not restricted to the lower part of
the crypts.
Cuboidal cells with eosinophilic cytoplasm, Rare 12%
frequent mitotic figures, marked nuclear atypia
with vesicular nuclei and prominent nucleoli
Cells with amphophilic or basophilic cytoplasm, Rare 8%
elongated hyperchromatic nuclei and variable
amount of goblet cell differentiation resembling
cells from conventional adenomas

adenoma and can be encountered in other subtypes of
colonic polyps.
Traditional serrated adenoma is much less common than
sessile serrated polyp, representing up to 2% of all color-
ectal polyps from various series depending on diagnostic
criteria [36]. The prevalence of traditional serrated adenoma
is probably an underestimate as advanced traditional ser-
rated adenoma may resemble conventional adenoma, and
flat traditional serrated adenoma is often reported as sessile
serrated polyp with dysplasia. Both males and females are
equally affected, usually in the sixth or seventh decade [37–
42]. The prototypical traditional serrated adenoma is a large
protuberant polyp in the distal colon or rectum with villi-
form architecture, uniform cytology, slit-like serration, and
ectopic crypt foci (Fig. 5). The characteristic traditional
serrated adenoma cells have abundant and intensely eosi-
nophilic cytoplasm, bland oval palisaded nuclei without
mitotic activity or Ki-67 positivity by immunohistochem-
istry [37, 41, 43]. It is unclear what proportion of the polyp
needs to have the traditional serrated adenoma cytology for
the diagnosis. If the other two histological features of tra-
ditional serrated adenoma are present, focal traditional ser-
rated adenoma cytology may be sufficient for the diagnosis.
Some traditional serrated adenomas with typical slit-like
serration and at least focal ectopic crypt foci may have a
predominance of goblet cells (mucin rich variant) [44, 45].
Another confusing point is the presence of superimposed
intestinal dysplasia that can arise in an advanced traditional
serrated adenoma, completely replacing the original epi-
thelial lining and mimicking a tubulovillous adenoma (see
discussion below).
The second and probably most typical feature of tradi-
tional serrated adenoma is the distinctive type of serration
(slit-like serration), reminiscent of the narrow slits in the
normal small intestinal mucosa [36, 37]. (Fig. 5). The
association of both the traditional serrated adenoma cytol-
ogy and slit-like serrations makes the diagnosis of tradi-
tional serrated adenoma straightforward.
Ectopic crypt foci are small buds of epithelial cells
resembling the bases of normal crypts, not anchored to the
muscularis mucosae, and found along the villous projec-
tions of the polyp (Fig. 5) [22]. When multiple, they may be
misinterpreted as superimposed dysplasia on cross section.
Rather than specific of traditional serrated adenoma, ectopic
crypt foci may represent small proliferation zones in polyps
with villiform growth pattern, including some tubulovillous
adenomas [46, 47]. Moreover, flat traditional serrated ade-
nomas may lack ectopic crypt foci. Ectopic crypt foci are
therefore not an absolute prerequisite for the diagnosis of
traditional serrated adenoma.
In up to 50% of traditional serrated adenomas, an adja-
cent polyp is identified which may represent a precursor
lesion [37, 39, 40, 48]. (Fig. 5) The fact that traditional
serrated adenoma may represent adenomatous transforma-
tion in a hyperplastic polyp was alluded to in the seminal
paper by Longacre et al. [7] and was preceded by a similar
suggestion in 1970 by Goldman et al. [49]. Proximal flat
traditional serrated adenomas are more likely to harbor a
BRAF mutation and to have an adjacent microvesicular
hyperplastic polyp or a sessile serrated polyp. Distal tradi-
tional serrated adenomas are often KRAS-mutated and may
have a ‘shoulder’ area of flat traditional serrated adenoma at
the edge of a large protuberant lesion. A goblet cell
hyperplastic polyp can also sometimes be found, suggesting
that some KRAS-mutated traditional serrated adenomas may
arise from a goblet cell hyperplastic polyp. In a recent
study, small (<10 mm) polyps resembling the shoulder area
seen in large protuberant traditional serrated adenomas were
An update on the morphology and molecular pathology of serrated colorectal polyps and associated. . . 1399

Fig. 5 Traditional serrated

adenoma. a–b The most typical
feature of traditional serrated
adenoma (b) is the distinctive
type of serration (slit-like
serration, arrow), reminiscent of
the narrow slits in the normal
small intestinal mucosa (a).
Ectopic crypt foci (arrowhead)
and columnar cells with
prominent eosinophilic
cytoplasm are also seen (b).
c Large protuberant traditional
serrated adenoma with villiform
growth. d. A small protuberant
traditional serrated adenoma
with an identifiable adjacent
precursor lesion. e Some
traditional serrated adenomas are
flat as in this example. Flat
traditional serrated adenomas are
often associated with a precursor
sessile serrated polyp and
located in the right colon.
f Mucin-rich traditional serrated
adenoma

shown to be the early forms of traditional serrated adenoma Serrated adenoma-unclassified

[50]. Like larger traditional serrated adenomas, these small
lesions are characterized by at least 2 of the features
of traditional serrated adenoma: slit-like serrations, typical
cytology, and ectopic crypt foci.
Despite being a polyp with malignant potential, ordinary
traditional serrated adenomas do not have the cytological
characteristics of the usual type of dysplasia as seen in the
colon. However, overt dysplasia develops when traditional
serrated adenomas progress to advanced lesions. This
superimposed dysplasia can be either of intestinal type
resembling dysplasia seen in conventional adenoma or of
serrated type as seen in sessile serrated polyp progressing to
serrated type dysplasia [37, 39–41, 43]. (Fig. 6) There are
currently no specific surveillance guidelines when super-
imposed dysplasia is diagnosed in a traditional serrated
adenoma. We recommend that high grade intestinal dys-
plasia and serrated dysplasia should be reported as this
heralds an advanced stage of the lesion.
It has become clear over the past few years that some
dysplastic serrated polyps do not fit neatly into traditional
serrated adenoma or sessile serrated polyp with dysplasia
or conventional adenoma. In particular, some adenomas
that lack the cytologic features of traditional serrated ade-
noma can demonstrate serrated morphology. These have
been termed serrated tubulovillous adenomas by some
authors (Fig. 7) [45, 46]. These polyps demonstrate mole-
cular features intermediate between traditional serrated
adenoma and conventional tubulovillous adenoma. Other
polyps may consist predominately of conventional tubu-
lovillous adenoma with only focal features suggestive but
not entirely diagnostic of a traditional serrated adenoma.
Some of these polyps may represent traditional serrated
adenomas overgrown by conventional dysplasia, but
uncertainty exists as to the diagnosis. In one study, re-
review of 180 distal villous and tubulovillous adenomas
1400
Fig. 6 Traditional serrated adenoma with superimposed dysplasia. a
Large protuberant traditional serrated adenoma with areas of high-
grade dysplasia (b)
Fig. 7 Serrated adenoma-unclassified. An adenoma with serrated
architecture and ectopic crypt foci that lack characteristic cytologic
features of a traditional serrated adenoma
resulted in re-classification of 20 polyps as traditional
serrated adenoma indicating histologic overlap between
these polyp types [47, 48]. Finally, sessile serrated polyps
with small areas of eosinophilic cells can be confusing to
classify. These sessile serrated polyps have been regarded
as having either low-grade serrated dysplasia, features of
traditional serrated adenoma, or “enteric metaplasia” (see
discussion below) by various authors. Given the uncer-
tainties in the classification of these serrated polyps, the
term “serrated adenoma, unclassified” is proposed. In our
opinion this term should be used sparingly.
R. K. Pai et al.
Differential diagnosis and controversial issues
Sessile serrated polyp versus hyperplastic polyp
The major differential diagnosis of sessile serrated polyp is
with a microvesicular hyperplastic polyp and this distinction
continues to be problematic [51–53]. This is true not only in
the community setting but even among subspecialized
pathologists with an interest in serrated polyps. In a recent
population-based study from Denmark, nearly 25% of all
serrated polyps were excluded from the study because they
could not be classified into hyperplastic polyp or sessile
serrated polyp with certainty by four expert gastrointestinal
pathologists [54]. The current recommendations suggest
that a polyp with one classical sessile serrated polyp-type
crypt is sufficient to render the diagnosis of a sessile ser-
rated polyp over a microvesicular hyperplastic polyp
[9, 10]. It should be emphasized that when making the
assessment on a single crypt, the changes should be overt
and the polyp free of prolapse effect which can induce
spurious crypt architectural abnormalities (Fig. 8) [55, 56].
In equivocal cases deeper levels can often be informative as
more classical sessile serrated polyp-type architectural
changes may become apparent.
It is important to emphasize that the size, location,
number, and endoscopic appearance are not part of the
pathological diagnosis of a hyperplastic polyp or a sessile
serrated polyp. Using these parameters can hamper future
efforts to refine the risk profile of patients with serrated
polyps, especially in scenarios such as small proximal
hyperplastic polyps or large distal hyperplastic polyps. Only
a proper morphologic classification of serrated polyps that is
reproducible amongst practicing pathologists will allow
further refinement of the risk of metachronous neoplasia in
these patients. Results from such analyses can then be used
to modify the diagnostic criteria if necessary.
From a practical perspective, it is exceedingly rare to
encounter a microvesicular hyperplastic polyp >10 mm and
such polyps should be considered advanced serrated polyps
for the purposes of deciding subsequent surveillance inter-
vals and ensuring complete resection. The main dilemma
occurs when encountering small or dimunitive proximal
serrated polyps that morphologically are best classified as
microvesicular hyperplastic polyp (Fig. 8). Furthermore,
goblet cell hyperplastic polyps are frequently seen in the
proximal colon. There has been a tendency to consider all
proximal serrated polyps as sessile serrated polyp, despite
the lack of diagnostic features, due to the presumption that
hyperplastic polyps do not exist in the proximal colon. Such
a strategy will lead to increased frequency of colonoscopy
for these patients and an increased burden on already busy
surveillance programs. In rare cases of polyps with marginal
histological features, size and location can be used to tip the
An update on the morphology and molecular pathology of serrated colorectal polyps and associated. . . 1401

Fig. 8 Diagnostic issues in the

diagnosis of hyperplastic polyp
and sessile serrated polyp. a A
proximal microvesicular
hyperplastic polyp can be
confidently diagnosed if the
polyp is well-oriented and no
characteristic sessile serrated
polyp-type crypts are present.
b A proximal goblet cell
hyperplastic polyp with subtle
superficial serrations and goblet
cell rich epithelium. c A
diminutive sessile serrated polyp
with a single unequivocal
architecturally abnormal crypt.
d A microvesicular hyperplastic
polyp with prominent mucosal
prolapse resulting in abnormal
crypt architecture that could
mimic a sessile serrated polyp

diagnosis one way or another. In general, we try to avoid
using diagnoses such as indeterminate serrated polyp, as
they are unhelpful to the clinician. In our experience such a
diagnosis is almost always managed as per a sessile
serrated polyp.
Significance of eosinophilic cells in various serrated polyps
One of the most controversial points in serrated polyp
diagnosis is the significance of traditional serrated
adenoma-type cells in various colonic lesions. The appear-
ance is reminiscent of absorptive cells in the normal small
bowel with narrow slits along the epithelium and a brush
border on the apical surface [57]. For these reasons, this
phenotype has been called by some authors enteric meta-
plasia, which have characteristics of senescent cells rather
than dysplastic cells [34]. However, others consider that the
presence of this cell type in a serrated polyp represents a
form of serrated dysplasia and should be reported as sessile
serrated polyp with traditional serrated adenoma-like dys-
plasia or low-grade serrated dysplasia. The different opi-
nions add to the confusion in the differential diagnosis
between traditional serrated adenoma and sessile serrated
polyp with dysplasia. We recommend that the term ‘serrated
dysplasia’ should only be used for the “high-grade” dys-
plastic changes as described above, which are similar to the
cytological features of serrated adenocarcinomas of the
colon [58]. We believe the traditional serrated adenoma-
type cytology should not be classified as serrated dysplasia
and, if present in a sessile serrated polyp, should not be
interpreted as a sessile serrated polyp with (serrated) dys-
plasia. Further studies are needed to investigate whether
sessile serrated polyp with traditional serrated adenoma-like
cytology (or flat traditional serrated adenoma arising from a
sessile serrated polyp) have molecular features of traditional
serrated adenoma supporting the hypothesis that these
lesions are a form of traditional serrated adenoma or whe-
ther they represent a subtype of advanced sessile
serrated polyp.
Inflammatory pseudopolyps and mucosal prolapse of the
large intestine are common non-neoplastic lesions that can
exhibit the same eosinophilic cell changes as seen in tra-
ditional serrated adenoma (Fig. 9) (and also display some
serration mimicking a sessile serrated polyp or a traditional
serrated adenoma). The differential diagnosis between a
traditional serrated adenoma with prolapse changes and an
inflammatory pseudopolyp with prominent serration and
traditional serrated adenoma-type cytology can occasionally
be challenging. In the latter, the inflammation in the lamina
propria is usually more marked and crypts show more
obvious architectural distortion.
As mentioned, in some sessile serrated polyps, patches of
eosinophilic cell changes (focal enteric metaplasia) can be
present involving only parts of the superficial aspect of
crypts that otherwise show a typical sessile serrated polyp
morphology (Fig. 9). This most likely represents a reactive
change in an ordinary sessile serrated polyp. The difficulty
arises with the differential diagnosis of flat traditional
1402
Fig. 9 Mimics of traditional serrated adenoma. a An inflammatory
polyp with focal serrated morphology and enteric metaplasia. b Enteric
metaplasia on the surface epithelium of a sessile serrated polyp. This
change should not be regarded as evidence of a traditional serrated
adenoma
serrated adenoma. Compared with sessile serrated polyps
showing focal enteric metaplasia, flat traditional serrated
adenomas demonstrate a traditional serrated adenoma-type
cytology covering the entire luminal aspect of the lesion and
often extending toward the crypt bases. Another histologic
feature of traditional serrated adenoma needs to be present.
In flat traditional serrated adenoma, slit-like serration is
most commonly seen. Ectopic crypt foci are rarely present
in flat traditional serrated adenomas while it is a feature of
protuberant traditional serrated adenomas. While this
approach can resolve the diagnostic dilemma for most
lesions, some still defy proper categorization. As men-
tioned, a diagnosis of serrated adenoma-unclassified can be
appropriate in this setting.
Grading dysplasia in sessile serrated polyps
Throughout the gastrointestinal tract, dysplasia is graded
using a two-tiered system. However, grading dysplasia in
R. K. Pai et al.
sessile serrated polyp is not recommended for multiple
reasons. First, cytoarchitectural features used to grade dys-
plasia may not be applicable to dysplastic sessile serrated
polyps given the wide morphologic heterogeneity. Fur-
thermore, there has not been a study measuring the inter-
observer agreement in the grading of dysplasia in sessile
serrated polyp. More importantly, MLH1 loss is seen in
dysplastic areas that are histologically quite bland. Loss of
MLH1 expression in a dysplastic area indicates a lesion that
has acquired a microsatellite instability phenotype and is at
high-risk of rapid progression to invasive carcinoma. Given
that MLH1 loss does not reliably correlate with traditional
grades of dysplasia, grading does not adequately reflect the
malignant potential of these lesions.
Advances in the molecular pathology of the
serrated neoplasia pathway
The serrated neoplasia pathway, like most neoplastic path-
ways, is complex. The hallmarks are MAP kinase pathway
activation (especially by BRAF mutation) and the CpG
island methylator phenotype. These changes tend to occur
early in polyp development. From a conceptual viewpoint,
serrated lesions can be broadly divided into early, advanced
and malignant. Early polyps include microvesicular hyper-
plastic polyp, goblet cell hyperplastic polyp, sessile serrated
polyp and potentially (depending on individual preference)
traditional serrated adenoma. Advanced polyps then include
sessile serrated polyp with dysplasia and traditional serrated
adenoma with high grade dysplasia. These culminate in
serrated pathway carcinomas. The natural history of serrated
pathway carcinomas is remarkably variable depending on
the molecular events that have resulted in malignant trans-
formation. Figure 10 is a schematic of the major routes to
serrated carcinoma arising from serrated polyps.
Early serrated polyps
Microvesicular hyperplastic polyp and sessile serrated
polyp have overlapping molecular alterations. Most micro-
vesicular hyperplastic polyps and sessile serrated polyps
harbor an activating BRAF mutation [59, 60]. In contrast
relatively few microvesicular hyperplastic polyps are CpG
island methylator phenotype-high (10%) versus 40–50% of
sessile serrated polyps [59, 60]. Currently there is no reli-
able molecular marker that can distinguish these lesions and
despite the imperfections discussed above, histology is
currently considered the gold standard. Whether sessile
serrated polyps arise de novo or from microvesicular
hyperplastic polyps still remains a matter of debate, but if a
microvesicular hyperplastic polyp does transition to a ses-
sile serrated polyp, the driver(s) of this change are not clear.
The molecular changes that occur in goblet cell hyperplastic
An update on the morphology and molecular pathology of serrated colorectal polyps and associated. . .
Fig. 10 Schematic of the serrated neoplasia pathway. Most sessile
serrated polyps harbor a BRAF mutation and may develop possibly
from a microvesicular hyperplastic polyp or de novo (dotted line).
Sessile serrated polyps progress to malignancy by either acquiring
mismatch repair deficiency caused by MLH1 promoter methylation or
through other molecular events such as TP53 mutation to mismatch
repair-proficient colorectal carcinoma. Traditional serrated adenoma
polyps are less well described but KRAS mutations have
been observed. Furthermore, a recent study has suggested
that goblet cell content in non-dysplastic serrated polyps is
predictive of KRAS alterations [61].
Whether the traditional serrated adenoma should be
included in the non-dysplastic group is unsettled. Most
authors would consider these lesions to have low grade
dysplasia. However, the cytology is bland and proliferation
is limited [37]. Regardless, traditional serrated adenomas
appear to have more molecular alterations at this initial
stage than either microvesicular hyperplastic polyps or
sessile serrated polyps. The majority show MAP kinase
activation with around 50% having a BRAF mutation and
30% a KRAS mutation [37, 38, 43]. CpG island methylator
phenotype-high is common in the BRAF mutated polyps but
is less frequent in the KRAS mutated cases [37].
While many of the BRAF mutated traditional serrated ade-
nomas arise from sessile serrated polyps and microvesicular
hyperplastic polyps, the origins of the KRAS mutated cases
are more obscure; however, two recent publications suggest
they may arise de novo or from a similar appearing pre-
cursor [50, 62]. Additional mutations in traditional serrated
adenomas without overt dysplasia have recently been
demonstrated in several excellent publications from Japan
by Sekine and co-authors [63, 64]. They have shown that
KRAS mutated traditional serrated adenomas have fairly
1403
may develop possibly from sessile serrated polyp or some goblet cell
hyperplastic polyps (dotted lines) and progress to malignancy via the
BRAF or the KRAS pathway to high grade dysplasia and mismatch
repair proficient-colorectal carcinoma. WNT signaling pathway acti-
vation occurs in all pathways through different mechanisms, at the
transition to dysplasia or earlier in traditional serrated adenoma
frequent RSPO fusion transcripts and that BRAF mutated
traditional serrated adenomas have quite frequent RNF43
mutations. In addition, the authors have demonstrated that
these molecular alterations tend to occur at the transition
from precursor polyp (e.g., microvesicular hyperplastic
polyp or sessile serrated polyp) to traditional serrated ade-
noma [65].
Advanced serrated polyps
The two categories of advanced serrated polyp are the
sessile serrated polyp with dysplasia and traditional serrated
adenoma with superimposed dysplasia. Both are recognized
by a transition to overt dysplasia in a discrete area of the
polyp. The sessile serrated polyp with dysplasia is the most
intensively studied of the two groups. Methylation induced
silencing of the MLH1 gene is the most recognized mole-
cular event occurring in these lesions. The frequency of this
occurrence is quite variable in the literature, ranging from
15–73% [30, 66]. In our opinion, the lower values reflect
inclusion of sessile serrated polyps with enteric metaplasia
or early and flat traditional serrated adenoma within the
sessile serrated polyp with the dysplasia group. These early
and flat traditional serrated adenomas are often recorded as
so-called low-grade serrated dysplasia. We do not consider
these polyps to represent true sessile serrated polyp with
1404
dysplasia and in a recent publication where these cases were
not included, 73% of cases were mismatch repair deficient
[27]. This value is more reflective of the mismatch repair
status in BRAF mutated carcinomas, where the majority are
also mismatch repair deficient. Other molecular events are
also critical to the progression from sessile serrated polyp to
carcinoma. Several studies have demonstrated silencing of
the critical tumor suppressor genes p16 and TP53 mutation
in a significant minority of cases [27, 67, 68]. WNT path-
way activation is also frequent, however in contrast to the
chromosomal instability pathway, WNT pathway activation
tends to occur later in serrated polyps. In addition, APC
mutation is less common in the serrated pathway [69].
Instead methylation induced silencing of WNT antagonists
such as the SFRP genes, AXIN2 and MCC all play a role
[70].
By contrast there is effectively never loss of MLH1
expression in the transition of traditional serrated adenoma
to high grade dysplasia [43]. As discussed above, RNF43
mutation and RSPO fusions are common early events in
traditional serrated adenomas. Similar to the sessile serrated
polyp with dysplasia, loss of p16 expression and TP53
mutation are relatively common at the transition to high-
grade dysplasia [37].
Risk of metachronous and synchronous neoplasia in
patients with serrated polyps
The original description of sessile serrated polyp as a his-
tological entity was not based on any longitudinal outcome
data. Subsequent studies to determine the surveillance
implications of a diagnosis of sessile serrated polyp have
been hampered by diagnostic variability. Consequently,
current guidelines for surveillance in patients with serrated
polyps contain recommendations based on limited data
[10, 71]. The distinction of hyperplastic polyp from sessile
serrated polyp continues to be problematic and confounds
longitudinal studies attempting to assess neoplastic risk
based on histologic subtype of serrated polyp [51–53].
Concurrent conventional adenomas in patients with serrated
polyps are confounding factors that must be adjusted for in
outcome studies but this is often not feasible outside the
setting of a large multi-institutional or population-based
study. In a study of US male veterans, patients with prox-
imal serrated polyps (hyperplastic polyp and sessile serrated
polyp combined) were twice as likely to have concurrent
conventional advanced or multiple (≥3) adenomas and those
with large (≥10 mm) serrated polyps were over three times
as likely to have concurrent advanced adenomas [72]. This
association has been confirmed in several studies and holds
true even when the serrated polyps are sub-classified into
hyperplastic polyp or sessile serrated polyp [73]. In fact,
presence of a synchronous advanced adenoma makes it
R. K. Pai et al.
more than twice as likely that a hyperplastic polyp from the
pre-sessile serrated polyp era will be re-classified as a ses-
sile serrated polyp upon review [74]. Moreover, multiple
polyps occur over time in patients undergoing surveillance
colonoscopy. It is difficult to ascribe the subsequent cancer
risk to a particular histologic type of precursor lesion in
such patients unless the study sample size permits an ade-
quate regression analysis. Certain polyp characteristics may
alter the subsequent risk of colorectal carcinoma. Patients
with large polyps are more likely to undergo a careful and
thorough examination leading to “detection bias” where
other concurrent polyps are more likely to be detected and
removed during the procedure. This lowers the risk of
subsequent colorectal carcinoma in these patients even
though they may harbor precursor lesions at significant risk
of malignant transformation. Similarly, patients with
advanced and/or multiple conventional adenomas undergo
close surveillance and metachronous risk of colorectal car-
cinoma in these patients may appear spuriously lower
compared to low-risk patient groups that undergo surveil-
lance at longer intervals. Colorectal carcinoma is not com-
monly detected in patients undergoing surveillance
colonoscopy and markers of high risk, such as advanced
adenomas or large serrated polyps, are often used as sur-
rogate outcomes of interest in longitudinal outcomes stu-
dies. While these markers are indirectly helpful in
determining appropriate surveillance intervals they do not
represent the true outcome of interest in patients undergoing
surveillance colonoscopy, which is reduction in mortality
from colorectal carcinoma.
Despite the above limitations several conclusions can be
drawn based on published literature summarized in Table 3.
Serrated polyps without dysplasia are indeed a risk factor
for colorectal carcinoma in the long term but the short-term
risk of malignancy, at least in patients under surveillance,
appears to be low. In a retrospective study from a period
when sessile serrated polyps were all diagnosed as hyper-
plastic polyp, 23 large (≥10 mm) “hyperplastic polyp” left
in-situ did not progress to cancer over a median follow up of
11 years which argues against a fast progression to cancer
[75]. Similarly, in the study by Lu et al. on patients with
sessile serrated polyp, the reported risk of incident color-
ectal carcinoma was much higher (12.5%) than other stu-
dies, but even they reported a median interval of 8.3 years
between the detection of sessile serrated polyp and the
eventual diagnosis of colorectal carcinoma [76]. There have
also been suggestions that serrated polyps may play a larger
than expected role in the development of interval colon
cancers [77]. However, interval colorectal carcinomas are
more common in the proximal colon where mismatch repair
deficient tumors are more prevalent. Once location is mat-
ched between sporadic interval and non-interval colon
cancers, the genetic landscape of both groups of tumors
Table 3 Risk of metachronous and synchronous lesions stratified by serrated polyp subtype
Study Design Patient population (n) n (total/ Outcome of Salient findings Follow up duration Limitations
serrated interest
polyps)

Bensen Prospective, post-hoc
SP et al., analysis
[90]
Lazarus R Retrospective
et al., [91] longitudinal
Laiyemo Prospective, post-hoc
AO et al., analysis
[92]
Schreiner Prospective, post-hoc
MA et al., analysis
[72]
Lu F-I Retrospective, case
et al., [76] control
Patients from 2 large polyp 1583/
chemoprevention trials 294
Consecutive patients 239/101 Hyperplastic Hyperplastic polyp on index predictive 94 months (mean) Small number of patients; no sessile
diagnosed with hyperplastic
polyp, serrated or
conventional adenomas
Patients with prior adenoma 1637/
on polyp prevention trial 437
US veterans in a large 3121/
multicenter screening trial 801
Patients diagnosed with 1583/
hyperplastic polyp at 294
University Hospital between
1980 and 2001
Hyperplastic Hyperplastic polyp on index predictive 3 years after index Pre-sessile serrated polyp era; no
polyp or any of metachronous hyperplastic polyp
adenoma (OR = 3.67; 2.54–5.31) but not
adenoma
polyp or any of metachronous hyperplastic polyp but
adenoma not adenoma (93% versus 5.3)
Any Index hyperplastic polyp (proximal or 3 years
adenoma distal) not associated with
metachronous adenoma (OR = 1.19;
0.94–1.51) or advanced adenoma (OR
= 1.25; 0.78–2.03)
Advanced Proximal and large serrated polyps 2-3 <5.5 years
adenoma times more likely to be associated with
concurrent advanced adenoma; patients
with concurrent proximal serrated
polyp and advanced adenoma at
baseline twice as likely to develop
advanced adenoma on surveillance
compared to advanced adenoma alone
Adenoma 5.8% of all hyperplastic polyps 4.8–13.2 years
with high- reclassified as sessile serrated polyps; 5
grade (12.5%) developed colorectal cancer;
dysplasia or 11 patients with large (≥1 cm) sessile
colorectal serrated polyp but none developed
cancer cancer or high-grade lesions on follow
stratification by hyperplastic polyp
location/size
serrated polyp diagnoses; only 49.4%
had complete colonoscopy on index
examination
Only 132 patients with proximal
hyperplastic polyp; no sessile serrated
polyp diagnosis; size not considered as
exposure variable; majority
hyperplastic polyp diminutive in size
Hyperplastic polyp and sessile serrated
polyp considered as one group; size not
considered as exposure variable due to
small number of large serrated polyps
(n = 31)
Only one patient presented for general
screening, the remaining for symptoms
or personal or family history of
colorectal cancer; unclear whether full
colonoscopy performed at index
examination in all patients; no analysis
An update on the morphology and molecular pathology of serrated colorectal polyps and associated. . .

up to determine impact of polyp, type,

Holme O Prospective Patient’s enrolled in the 12,955/
et al., [75] longitudinal Norwegian colorectal cancer 81
prevention trial
Macaron Prospective cohort Patients with large 255/157 Advanced
C et al., hyperplastic polyp, any
[88] sessile serrated polyp or
traditional serrated adenoma
location, number
Colorectal Large serrated polyp, large adenoma 10.9 years Only 81 large serrated polyps and only
cancer and multiple adenomas were (median) 3 cancers in this group on follow up;
independent risk factors on 21% polyps not classified into
multivariable analysis; no cancer hyperplastic polyp or sessile serrated
developed in 23 large serrated polyps polyp; impact of histologic diagnosis
left in-situ at screening for median 11 not assessed
years
Metachronous large serrated polyps 46.8 months Small number of cases; only 28%
adenoma or exclusively in patients with index (median) followed up for entire 5 years; included
advanced serrated polyps; metachronous dysplastic sessile serrated polyp and
advanced adenomas on follow up more traditional serrated adenoma at baseline
1405
Table 3 (continued)
1406

Study Design Patient population (n) n (total/ Outcome of Salient findings Follow up duration Limitations
serrated interest
polyps)

at baseline colonoscopy at a serrated likely in patients with advanced

Yoon JY Retrospective, case
et al., [99] control
Erichsen Nested case control
R et al.,
[54]
Melson J Retrospective
et al., [97] longitudinal
Pereyra L Retrospective
et al., [93] longitudinal
Egoavil C Retrospective sub-
et al., [87] analysis of patients with 24 different hospitals
tertiary center
Korean patients with 558/186 Advanced
traditional serrated adenoma
or conventional adenoma
Danish population database
with and without colorectal
cancer
Patients over a 6-year period 788/166 Advanced
at academic medical center
Screening colonoscopy
patients at teaching hospital
Nationwide study involving 567/198 Colorectal
polyp adenomas at baseline colonoscopy with
or without concurrent serrated polyps
Risk of metachronous advanced 41.4–43.4 months 420 patients with traditional serrated
adenoma, adenoma, serrated adenoma and (mean)
serrated hyperplastic polyp in baseline
adenoma, traditional serrated adenoma patients
and was higher than those with baseline
hyperplastic conventional adenomas (OR 2.37 for
polyp advanced adenoma)
10,150/ Colorectal Sessile serrated polyp a risk factor for Mean 5.9 years
931 cancer colorectal cancer (OR = 3.07;
2.20–4.10); sessile serrated polyp
proximal to splenic flexure (OR =
12.42; 4.88–31.58) and traditional
serrated adenoma (OR = 4.84;
2.36–9.93) highest risk factors for
colorectal cancer
Metachronous advanced adenoma 40–54 months
adenoma or more frequent in patients with low-risk
large (>1 cm) adenoma and sessile serrated polyp
sessile (18.2%) compared to patients with
serrated low-risk adenoma alone (7.8%); and in
polyp high-risk adenoma with sessile serrated
polyp (31.9%) than with high-risk
adenoma alone (15.9%); metachronous
sessile serrated polyp more common in
patients with sessile serrated polyp at
baseline (33.1%) compared to those
with no sessile serrated polyp (5.0%)
639/75 Advanced Sessile serrated polyp patients with 54.5 months
adenoma or synchronous high-risk adenoma on (mean)
multiple index had higher incidence of
adenomas metachronous advanced adenoma
(12.96 per 1000 person-months)
compared to high risk adenoma alone
(5.07 per 1000 person–months);
Incidence of colorectal cancer in 4.2 years (mean)
cancer in confirmed serrated polyposis patients
adenoma were originally included but
follow-up was only available in 186.
Korean population only; may not be
applicable to other groups
Screening colonoscopy was not being
routinely performed in Denmark during
the study period which limits
applicability; polypoid dysplasia in
incident inflammatory bowel disease
also included; size of serrated polyps
and high-risk adenomas not accounted
for in the study; 24.9% serrated lesions
could not be classified into hyperplastic
polyp or sessile serrated polyp
Small number of cases; no category of
sessile serrated polyp alone;
hyperplastic polyp included; location
and size of serrated polyps not
analyzed; traditional serrated adenoma
considered a high-risk lesion
Small numbers, 47 patients in sessile
serrated polyp only group
Serrated polyp histology and size and
presence of concurrent conventional
R. K. Pai et al.
Table 3 (continued)
Study Design Patient population (n) n (total/ Outcome of Salient findings Follow up duration Limitations
serrated interest
polyps)

multiple serrated polyps patients and similar to those in patients with adenomas not incorporated in analysis
that did not fulfill their first- multiple serrated (>50% of total) even though the multiple serrated
criteria for serrated degree polyps and their first-degree relatives polyp group had higher median number
polyposis relatives of adenomas than the serrated
polyposis group; arbitrary criterion for
defining “multiple” serrated polyps
Anderson Retrospective Statewide population-based 5433/ Advanced or Metachronous large (>1 cm) serrated 4.9 years (median) Small number of patients in the high-
JC et al., longitudinal registry data analysis 1016 multiple polyp best predicted by index large risk group of concurrent high-risk
[89] adenomas or serrated polyp (hyperplastic polyp or adenoma and sessile serrated polyp or
cancer sessile serrated polyp; OR 14.34) and traditional serrated adenoma;
sessile serrated polyp histology (OR traditional serrated adenoma not
9.70); metachronous high-risk separated out as a distinct group for
conventional adenoma best predicted analysis
by baseline high-risk adenoma (OR
3.86); highest risk of metachronous
high-risk adenoma in patients with
concurrent high-risk adenoma and
sessile serrated polyp at baseline
colonoscopy (OR 16.04)
An update on the morphology and molecular pathology of serrated colorectal polyps and associated. . .
1407
1408
appears to be quite similar [78]. This suggests that interval
colon cancers are more likely to arise from missed lesions or
incompletely excised precursors rather than a distinct
pathogenetic pathway. This conclusion is also supported by
the prospective CARE (completeness of adenoma resection)
study that showed an overall incomplete polyp excision rate
of 10%. The incomplete resection rate increased to 17% for
large (10–20 mm) polyps, 31% overall for sessile serrated
polyp and nearly 50% for sessile serrated polyp larger than
10 mm [79]. The prevalence of missed lesions on colono-
scopy has been estimated to range from 2–13% [80, 81] but
a recent meta-analysis of over 15,000 tandem colonoscopies
estimated the average miss rates to be 26% for adenomas,
9% for advanced adenomas and 27% for serrated polyps
[82].
There is little evidence at this time to suggest that his-
tologic subtype of serrated polyp carries a predictive value
for metachronous advanced outcomes independent of polyp
size, location and number although multiple studies using
centralized pathologic review with updated diagnostic cri-
teria have yet to be performed. Polyp size and location do
appear to be important predictors of risk for both concurrent
and subsequent advanced neoplasia and cancer. As men-
tioned above, cross-sectional studies have shown that ses-
sile serrated polyp and large hyperplastic polyp are
associated with synchronous multiple adenomas and
advanced adenomas and with additional synchronous large
sessile serrated polyp [72, 83–85]. A higher prevalence of
synchronous advanced adenomas occurs in patients with
large and proximal serrated polyps [83, 86] and large distal
serrated polyps are reported to be four times more likely to
be associated with proximal adenocarcinoma [86] empha-
sizing the importance of polyp size in serrated polyp risk
stratification. A recent nationwide multi-institutional study
evaluated outcomes in patients with multiple (>50% of
total) serrated polyps who did not meet the criteria for
serrated polyposis. The incident risk of colorectal carcinoma
in these patients, and their first-degree relatives, was similar
to confirmed serrated polyposis patients, suggesting an
increased cancer risk with increasing cumulative number of
serrated polyps [87].
There also seems to be emerging consensus that patients
with high risk conventional adenomas (≥3 in number, ≥10
mm in size, or those with a villous component or high-grade
dysplasia) and/or large serrated polyps can be binned into
three distinct risk groups. Patients with only high-risk con-
ventional adenomas at baseline are more likely to develop
subsequent high-risk adenomas on surveillance but not large
serrated polyps [54, 88, 89]. Conversely, patients with large
(≥10 mm) serrated polyps or those with sessile serrated
polyp histology, are more likely to develop large serrated
polyps on surveillance but not high-risk conventional ade-
nomas [88, 89]. This finding is similar to that reported in
R. K. Pai et al.
prior literature where index hyperplastic polyps were
reported to be predictive of subsequent hyperplastic polyps
but not conventional adenomas [90–92]. Interestingly, the
highest risk for metachronous high-risk conventional ade-
nomas seems to be in patients who harbor both high-risk
conventional adenomas and large serrated polyps at baseline
colonoscopy [72, 89, 93]. This last group of patients seem to
possess a background colonic mucosa prone to development
of neoplastic polyps along multiple pathways and are likely
to benefit the most from close surveillance. This finding in
the sporadic setting is analogous to patients with serrated
polyposis in whom the risk of colorectal carcinoma is not
only associated with the type or number of serrated polyp
but also the presence of concurrent conventional adenomas
[94–96]. Similarly, there is some data to suggest that
the metachronous risk of advanced neoplasia in patients with
low-risk adenomas and sessile serrated polyp is similar to
high-risk adenoma patients without any sessile serrated
polyp [97]. Patients with a diagnosis of sessile serrated polyp
may have a higher risk for metachronous large serrated
polyps compared to patients with large or proximal hyper-
plastic polyps (unpublished data). While this may reflect a
true biological difference between hyperplastic polyp and
sessile serrated polyp, this may also be due to sessile serrated
polyp being more likely to be missed or incompletely
excised on index examination and thus more likely to
develop large metachronous lesions.
Finally, the surveillance implications of a diagnosis of
traditional serrated adenoma also remain unclear given its
infrequent occurrence independent of other concurrent
polyps. An additional complication in recent years has been
an increasing trend to diagnose traditional serrated adenoma
as sessile serrated polyp with dysplasia when they occur in a
background of sessile serrated polyp or hyperplastic polyp,
a practice we discourage. Prior studies suggesting a high
risk of concurrent colorectal carcinoma and metachronous
adenomas in patients with baseline traditional serrated
adenoma were limited by small number of patients [91, 98].
More recently, in a relatively large study of Korean patients
with traditional serrated adenomas, the risk of metachronous
serrated polyps, conventional adenomas, as well as high-
risk adenomas was higher than a control population with
only baseline conventional adenomas [99]. A recent
population-based study from Denmark also showed patients
with traditional serrated adenoma to be nearly five times
more likely to develop colorectal carcinoma on follow up
[54]. However, this study included incident inflammatory
bowel disease-dysplasia patients, was from a time when
routine screening colonoscopy was not being performed in
Denmark, and despite the large sample size only 31 cases
and controls had a prior traditional serrated adenoma.
In summary, current evidence suggests that managing
large serrated polyps similar to low-risk adenomas is
An update on the morphology and molecular pathology of serrated colorectal polyps and associated. . .
adequate since the risk of cancer in the short term is low.
Close surveillance should be restricted to patients with
concurrent advanced adenomas and large serrated polyps.
Awareness of flat serrated precursor lesions in the right
colon will hopefully lead to greater emphasis on detection
and complete excision of these lesions and reduce the
metachronous risk of colorectal carcinoma in these patients
in the future.
Serrated polyposis
Serrated polyposis is a rare condition of largely unknown
etiology characterized by the development of multiple ser-
rated polyps in the large bowel. The upper gastrointestinal
tract and the small bowel are not affected [100]. Patients do
not have any extracolonic manifestation.
A familial component is well documented. About a third
of serrated polyposis patients have at least one first-degree
relative with colorectal carcinoma and 5% have a first-
degree relative with serrated polyposis [95, 96]. However,
no high-penetrance causative gene has been identified.
Approximately 2% of affected patients have a pathogenic
germline variant in RNF43, a gene involved in the WNT
signaling pathway [101–104].
Both genders are equally affected with most patients
diagnosed in their 5th or 6th decade [95, 96, 100, 105].
However, serrated polyposis may be identified in younger
adults. Because serrated polyps are less likely to bleed than
conventional adenomas, screening fecal blood tests do not
often lead to the diagnosis unless conventional adenomas or
advanced neoplasia are present.
The diagnostic criteria have been recently revised to
include patients who present with a predominantly distal
polyposis phenotype (including the sigmoid colon and the
rectum) [106]. In addition, the previous criterion 2 (any
number of serrated polyp proximal to the sigmoid colon in
an individual who had a first degree relative with serrated
polyposis) has been discarded.
The updated criteria for the diagnosis are:
Criterion 1: At least 5 serrated polyps proximal to the
rectum all ≥5 mm, with at least two ≥10 mm.
Criterion 2: More than 20 serrated polyps of any size but
distributed throughout the large bowel, with at least 5
proximal to the rectum.
Any histologic subtype of serrated polyp is included in
the final count. The diagnosis may require more than one
colonoscopy and the polyp count is cumulative over time.
Importantly, the phenotype is highly heterogeneous from
patients with low polyp burden to patients with large
numbers of polyps fulfilling both criteria and difficult to
manage by colonoscopy. Data from two large European
studies showed that 25% of patients meet only criterion 1
(type 1 phenotype), 45% meet only criterion 2 (type 2
1409
phenotype) and the remaining 30% have both phenotypes
[95, 96].
Patients with serrated polyposis have an increased risk of
colorectal carcinoma compared to the general population.
Results from two large retrospective studies showed that
colorectal carcinoma was diagnosed in 16% and 29% of
patients [95, 96]. In most cases, the diagnosis of cancer was
made before or at the time of serrated polyposis diagnosis.
Risk factors associated with colorectal carcinoma were (1)
the fulfillment of both clinical criteria; (2) more than 2 ses-
sile serrated polyps proximal to the splenic flexure; (3)
presence of at least one serrated polyp with dysplasia; (4)
presence of and at least one advanced conventional ade-
noma. Interestingly, nearly half of cancers were located in
the rectosigmoid, indicating that distal polyps are at risk of
progression and should be included in the diagnostic
criteria.
The molecular characterization of 45 serrated polyposis-
associated colorectal carcinomas showed that 46% harbored
a BRAF mutation, while KRAS mutation was rare (<5%).
MLH1 loss of expression was identified in 38% of cases
[107]. This suggests that not all cancers develop from ser-
rated polyps and that at least half may follow the conven-
tional adenoma-carcinoma pathway.
The diagnosis of serrated polyposis is frequently missed
[108, 109]. It is important for pathologists to know the
clinical criteria and make the diagnosis when all informa-
tion on polyp number and polyp size is available but may be
challenging when cumulative counts meet the criteria but
data from prior colonoscopies is not available. When a
patient has multiple serrated polyps but the exact location,
size and number are not clear, the pathologist should still
raise the possibility of serrated polyposis to prompt the
clinician to consider the diagnosis. Current surveillance
guidelines recommend referral to genetic counseling and
monitoring in tertiary centers [6, 10]. The aims are to
exclude rare known genetic syndromes that may present
with a serrated polyposis phenotype (MUTYH-associated
polyposis, hereditary mixed polyposis syndrome and
PTEN-hamartoma tumor syndrome), clear the entire large
bowel from polyps >3–5 mm in size, and undergo yearly
colonoscopy surveillance to prevent colorectal carcinoma. If
the polyp burden cannot be controlled by serial colo-
noscopies or if an advanced lesion is diagnosed, the patient
should be considered for surgery [6, 110]. Screening colo-
noscopy is recommended for first-degree relatives who have
5 times the incidence of colorectal carcinoma compared
with the general population [105, 111].
Serrated pathway associated carcinomas
The end point of these pathways is the development of
invasive malignancy (Fig. 11). Broadly, three major
1410
Fig. 11 Invasive carcinoma
arising from serrated precursors.
a, b An invasive carcinoma
arising from a sessile serrated
polyp with pushing margin, poor
differentiation and conspicuous
tumor infiltrating lymphocytes.
c, d An invasive carcinoma
arising from a traditional
serrated adenoma showing
infiltrative margin, serration in
glands, focal mucin and
eosinophilic tumor cells
Table 4 Colorectal carcinomas associated with serrated precursors
Type CpG methylation
BRAF mutated, mismatch repair deficient +++
KRAS mutated, mismatch repair proficient + Intermediate
BRAF mutated, mismatch repair proficient +++
BRAF/KRAS wild-type, mismatch repair +++
deficient
molecular subtypes of colorectal carcinoma can arise from
the serrated pathway including (1) BRAF mutated, mis-
match repair deficient; (2) BRAF mutated, mismatch repair
proficient; and (3) KRAS mutated, mismatch repair profi-
cient (Table 4) [112]. Serrated adenocarcinoma is a mor-
phologic variant recognized by the World Health
Organization characterized by epithelial serrations, eosino-
philic cytoplasm, vesicular nuclei, absence of necrosis, and
a mucinous or trabecular growth pattern. While this variant
can be reliably recognized histologically and likely arise
from malignant transformation of some sessile serrated
polyps and traditional serrated adenomas, most carcinomas
arising from serrated precursors do not have a serrated
adenocarcinoma morphology [58, 113].
BRAF mutated, mismatch repair deficient cancers have a
favorable prognosis and arise from sessile serrated polyp with
dysplasia that demonstrate loss of MLH1 (and PMS2)
expression [2, 114]. These tumors display classic features of
mismatch repair deficient colon cancers including medullary
R. K. Pai et al.
Prognosis Precursor Prevalence
Good Sessile serrated polyp 10–15%
Traditional serrated adenoma Unknown
Poor Sessile serrated polyp or traditional 5%
serrated adenoma
Good Sessile serrated polyp 5–0%
growth pattern, tumor infiltrating lymphocytes, mucinous
differentiation, and/or Crohn’s like peritumoral reaction. The
presence of a BRAF mutation and hypermethylation distin-
guishes these tumors from Lynch syndrome associated can-
cers. Mismatch repair deficient colon cancers demonstrate a
high tumor mutational burden and are amenable to treatment
with immune checkpoint inhibitors.
BRAF mutated mismatch repair proficient cancers have a
dismal prognosis and likely arise from the ~25% of sessile
serrated polyp with dysplasia that demonstrate retained
MLH1 expression and/or BRAF mutated traditional serrated
adenomas [115–119]. These tumors often present at an
advanced stage and may demonstrate an aberrant immu-
nophenotype with reduced CDX2 and cytokeratin 20
expression and increased cytokeratin 7 expression [118].
Histologically they may demonstrate partial mucinous dif-
ferentiation or neuroendocrine differentiation and often
have high-grade tumor budding, perineural invasion, and
extensive lymphovascular invasion [117].
An update on the morphology and molecular pathology of serrated colorectal polyps and associated. . .
KRAS mutated mismatch repair proficient tumors are
common and the vast majority likely arise through con-
ventional adenomas without evidence of CpG hyper-
methylation [2, 114]. A small subset of these tumors,
however, likely arise through KRAS mutated traditional
serrated adenomas and demonstrate low levels of CpG
island methylation [120]. Separating the subset of mismatch
repair proficient KRAS mutated tumors that arise from tra-
ditional serrated adenomas and from conventional adeno-
mas is difficult and studies comparing the two have yet to be
performed. It is interesting to note that methylation array
studies on colorectal carcinoma have shown not just two but
four distinct clusters [121]. It is remains to be seen whether
KRAS mutated mismatch repair proficient tumors arising
from traditional serrated adenomas and conventional ade-
nomas can be separated by virtue of their methylation
signatures.
A small but significant percentage of the colorectal car-
cinomas arising from a serrated precursor have an unusual
molecular phenotype. In particular, a ~25% of mismatch
repair deficient cancers lack BRAF mutations but will
demonstrate CpG island methylator phenotype-high with
hypermethylation of MLH1 [122–124]. The BRAF wild-
type mismatch repair deficient tumors may arise through the
small percentage of sessile serrated polyp that lack BRAF
mutations. These tumors behave similarly to BRAF mutated
mismatch repair deficient tumors. However, upto 30% of
these BRAF wild-type mismatch repair deficient cancers
harbor KRAS mutations [125]. The origin of the rare KRAS-
mutated mismatch repair deficient tumors is unclear
although when a precursor could be identified they histo-
logically resembled conventional tubular and tubulovillous
adenomas. The possibility that the serrated precursor was
overrun by the dysplastic component could not be entirely
excluded. Recently, Sekine and colleagues has identified a
small subset of sessile serrated polyp that harbor KRAS
mutations [61]. This finding has yet to be confirmed by
others but could potentially result in KRAS mutated mis-
match repair deficient tumors.
Conclusions
Serrated polyps are routinely encountered in colonoscopy
specimens and pose multiple diagnostic challenges. Over the
past few decades our improved understanding of these
polyps has resulted in refined diagnostic criteria for sessile
serrated polyp and traditional serrated adenoma. Multiple
morphologic subtypes of sessile serrated polyp with dys-
plasia have been recently recognized and correlated with
MLH1 expression. The molecular abnormalities seen in
serrated polyps have also been more fully characterized and
correlated with histologic subtype. Traditional serrated
1411
adenomas are the most molecularly heterogenous but
molecular heterogeneity also exists in sessile serrated polyps
with dysplasia. Finally, our knowledge of the risk of meta-
chronous and synchronous lesions in patients with serrated
polyps has expanded. Additional studies using strict diag-
nostic criteria will help us answer whether hyperplastic
polyp and sessile serrated polyp are two stages of the same
lesion or distinct entities and aid in further refining risk
stratification of subsequent neoplasia and development of
improved post-polypectomy surveillance guidelines.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Publisher’s note: Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
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